Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is characterized by a tendency for chronic or relapsing immune activation and inflammation within the gastrointestinal (GI) tract. With a prevalence of 2 cases per 1,000 people, IBD is increasingly becoming a significant problem in the Western world. The two major forms of IBD are Crohn’s disease and ulcerative colitis.
Ulcerative Colitis
Ulcerative colitis specifically affects the large intestine (colon) and results in characteristic ulcers or open sores. Cardinal symptoms include bloody diarrhea, abdominal pain, fever, obstruction, weight loss and an increased risk of colon cancer.
Ulcerative colitis is an intermittent disease, with silent and active periods, and has a yearly incidence of 3 to 15 per 100,000. The peak ages at diagnosis are 15-25 years and 55-65 years.
Ulcerative colitis can be associated with various complications outside of the colon, including ulcers in the mouth, inflammation of the iris, arthritis, inflammation of subcutaneous tissue, thrombosis and pulmonary embolism, and anemia.
Crohn’s Disease
Crohn’s disease is a condition of chronic inflammation, potentially involving any part of the alimentary tract from mouth to anus. Inflammation in Crohn’s disease often shows a banded pattern along the longitudinal axis of the gut.
Crohn’s disease has a yearly incidence of 4 to 10 per 100,000 and the peak age at diagnosis is 15-25 years. Affected persons usually experience the cardinal symptoms of diarrhea (or constipation), abdominal pain and often weight loss.
Frequent complications of Crohn’s disease include blockage of the intestine, sores that may affect surrounding tissue (bladder, vagina or skin), fistulas (tunnels) that often necessitate surgery and fissures (small tears in the lining of the mucosal membrane of the anus).
Etiology
The etiology of IBD is not completely understood, but it is believed to be an autoimmune disease with a certain genetic predisposition.
In healthy individuals, tight regulation of the immune system prevents excessive inflammatory responses towards normal intestinal bacteria. In IBD, the normal intestinal flora likely triggers inappropriate and ongoing activation of the mucosal immune system.
This pathological response is probably facilitated by defects in both the barrier function of the intestinal epithelium and in the mucosal immune system.
Standard Care
Pharmacological therapy, although generally effective in alleviating the symptoms, is not curative but focused on inducing and maintaining remission.
Standard care involves the administration of amino salicylic acid, corticosteroids or newer, biological medications. While there is no cure for Crohn’s disease, ulcerative colitis can be cured by surgical resection of the colon.
Recently, injectable treatments, including anti-TNF-alpha antibodies and antibody fragments, have been developed for the treatment of IBD. These biological drugs offer new options to patients in dire need of new therapeutic options.
Despite these recent introductions however, there still is a lack of orally available, safe and well-tolerated products for the treatment of IBD.
ActoGeniX’s Solution
ActoGeniX is developing AG014, an ActoBiotic™ expressing and secreting an anti-TNF-alpha Fab fragment for the treatment of inflammatory bowel disease. ActoGeniX has already obtained promising initial efficacy data for the effect of AG014 in a preclinical IBD disease model, demonstrating a significant reduction of colitis and associated inflammatory parameters.
AG014 is formulated as an enteric coated capsule, and is expected to combine excellent efficacy with a favorable safety profile. AG014 delivers the anti-TNF-alpha to the sites of mucosal inflammation in the colon and terminal ileum. AG014 is expected to combine the efficacy in IBD of injectable biological therapies such as anti-TNF-alpha antibodies with a much more favorable safety profile and no immunogenicity.
AG014 is expected to enter clinical proof of concept testing by the second half of 2012.
Furthermore, ActoGeniX is developing an ActoBiotic™ expressing and secreting the anti-inflammatory cytokine IL-27 for the treatment of inflammatory bowel disease and celiac disease. Positive efficacy data have been obtained with this product in an animal model of colitis. This groundbreaking work has been performed in collaboration with Professor Scott Durum at the National Cancer Institute (Frederick MD, US).